SGLT2 inhibitors and cardiovascular outcomes in heart failure with mildly reduced and preserved ejection fraction: A systematic review and meta-analysis

Aim: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: _x0001_50%) or/and mildly reduced EF (HFmrEF: 41e49%) regardless of baseline diabetes. Methods: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model. Results: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/ HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p < 0.001, I 2 ¼ 0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N ¼ 8891, HR 0.79, 95% CI: 0.71, 0.87, p < 0.001, I 2 ¼ 0%) and HFmrEF (N ¼ 4555, HR 0.77, 95% CI: 0.67, 0.89, p < 0.001, I 2 ¼ 40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N ¼ 6507, HR 0.80, 95% CI: 0.70, 0.91, p < 0.001, I 2 ¼ 0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p ¼ 0.08, I 2 ¼ 0%). Conclusions: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.

Efectos cardiovasculares de los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2): los mecanismos del beneficio en pacientes con insuficiencia cardíaca

La insuficiencia cardíaca (IC) es un problema de salud mundial. En la actualidad existe una clara asociación entre la IC y la diabetes mellitus tipo 2 (DM2), con una prevalencia cada vez mayor de pacientes que presentan concomitantemente ambas patologías. Los inhibidores del cotransportador 2 de sodio-glucosa (ISGLT2) han demostrado disminuir los eventos cardiovasculares, incluida la muerte de origen cardiovascular, por lo que se han instalado como uno de los pilares en su tratamiento. En el presente artículo se describen los principales mecanismos de acción de los ISGLT2 y sus efectos: mejora de condiciones de carga ventricular, metabolismo cardíaco, bioenergética, remodelado ventricular y sus efectos cardioprotectores directos y posiblemente antiarrítmicos.

Heart failure (HF) is a global health problem. Currently there is a clear association between HF and type 2 diabetes mellitus (DM2), with an increasing prevalence of patients presenting with both pathologies concomitantly. Sodium-glucose cotransporter 2 inhibitors (ISGLT2) have shown to significantly reduce cardiovascular events, including cardiovascular death. These results have placed ISGLT2 as one of the main pillars in the treatment of HF. This article will focus on the mechanisms of action, and their effects: improved ventricular loading conditions, cardiac metabolism, bioenergetics, ventricular remodeling, direct cardioprotective and possibly antiarrhythmic effects.

Sodium-glucose Co-transporter 2 Inhibitors: A Novel Molecule for Health Care Practitioners in Diabetology, Cardiology and Nephrology

Prevention and timely management of cardiovascular (CV) complications like myocardial infarction, heart failure (HF), stroke and renal complications, like chronic kidney disease (CKD) and end-stage renal disease, are important to improve the quality of life and survival in people with type 2 diabetes mellitus (T2DM). The multifaceted action of sodium-glucose co-transporter 2 inhibitors (SGLT2i) results in effective glycemic control with benefits on CV and renal risk factors, like body weight, blood pressure, uric acid and albuminuria. Robust CV and renal event reduction is reflected in the outcomes of large CV outcome trials, meta-analyses and real-world studies. Recent evidence has proven cardiac and renal benefits with SGLT2i in subjects with HF and CKD irrespective of their T2DM status. Until recently, SGLT2i was used as a glucose-lowering molecule with pleiotropic benefits, mainly by primary care practitioners and diabetologists. The potential for cardiac and renal protection in people with and without T2DM has shifted an interest in cardiologists and nephrologists to view it as a cardiac and renal molecule, respectively. Thus, the role of SGLT2i in the management of T2DM is undergoing a paradigm shift—straddling the interfaces of diabetology, cardiology, nephrology and primary care—moving away from being considered a pure antidiabetic molecule. We conducted a literature review of SGLT2i in management of T2DM along with their protective effects on CV and renal parameters in patients with or without baseline comorbidities.

DAPAGLIFLOZIN ASSOCIATED EUGLYCEMIC DIABETIC KETOACIDOSIS: A CASE REPORT

SGLT2 inhibitors are a new class of drugs for lowering blood sugar levels in type 2 diabetics. They have been shown to reduce cardiovascular risk along with improving glycemic control. Some of the SGLT2 inhibitors are Canagli?ozin, Dapagli?ozin, Empagli?ozin, Ertugli?ozin, Remogli?ozin. We are presenting a case of a 60-yearold female patient who is a known case of Type 2 Diabetes Mellitus presented to the emergency room with loss of responsiveness for 1 day gradual in onset. Her history revealed she is type 2 diabetic for the past 10yrs and was hospitalized 20days back when her RBS was 889mg/dl & urine ketones were positive with a diagnosis of type 2 DM with DKA. since then, she was put on Tab Dapagli?ozin 10mg OD along with other OHA's. On presentation, the patient was unconscious GCS-E1, V2, M2-5/15, pulse3 100/min, BP-80mm of hg systolic, glucometer RBS-211 mg/dl, ABG showed severe metabolic acidosis pH-6.86, HCO -2.9mmol/L, 2 PCO -24mm hg, PaO2-58mm hg, urine ketones came positive, and the patient was managed conservatively. The patient responded well, and her GCS improved with stabilization in her condition. Dapagli?ozin and other SGLT2 inhibitors can cause Euglycemic DKA, and these can be missed out in the emergency room as they have not so high blood sugar levels making the diagnosis of DKA dif?cult in emergency conditions

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

ABSTRACT The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI −0.66 to −0.59) and body weight by 0.60 kg (95% CI −0.64 to −0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Cardiovascular benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in type 2 diabetes: a systematic review and network meta-analysis / 药学实践杂志

Objective To evaluate cardiovascular benefits in patients with type 2 diabetes mellitus treated with the marketed 11 sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like polypeptide-1 (GLP-1) receptor agonism by Bayesian network meta-analysis system. Methods MEDLINE, Embase and Cochrane Library were searched from the establishment of the database to 18 July 2020. The endpoint of the study was adverse cardiovascular events. The effect measures were hazard ratios (HR) and 95% credible intervals (CI). Results Compared with placebo, empagliflozin, canagliflozin, dapagliflozin, albiglutide, dulaglutide, exenatide, liraglutide, semaglutide reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes with HR and 95% CI ranging between 0.75(0.60-0.95)~0.90(0.82-0.99); The risk of heart failure was reduced by empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, with HR and 95%CI ranging between 0.64(0.49-0.82)~0.74(0.65-0.85); Empagliflozin, canagliflozin, dapagliflozin, exenatide, liraglutide and oral semaglutide reduced the incidence of all-cause mortality with HR and 95%CI ranging between 0.52(0.33-0.84)~0.89(0.80-0.99); Empagliflozin, canagliflozin, liraglutide and oral semaglutide can reduce the risk of cardiovascular death events, with HR and 95% CI ranging between 0.54(0.30-0.95)~0.83(0.71-0.96) . Conclusion The order of the cardiovascular benefits of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes mellitus complicated with atherosclerotic cardiovascular disease are canagliflozin (the best), empagliflozin, dulaglutide, liraglutide; for patients with type 2 diabetes and heart failure. The order of the cardiovascular benefits for patients with type 2 diabetes and heart failure are empagliflozin, canagliflozin, ertugliflozin, and dapagliflozin.

Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular mortality in patients with diabetes mellitus but the protective mechanism remains elusive. Here we demonstrated that the SGLT2 inhibitor, Empagliflozin (EMPA), suppresses cardiomyocytes autosis (autophagic cell death) to confer cardioprotective effects. Using myocardial infarction (MI) mouse models with and without diabetes mellitus, EMPA treatment significantly reduced infarct size, and myocardial fibrosis, thereby leading to improved cardiac function and survival. In the context of ischemia and nutritional glucose deprivation where autosis is already highly stimulated, EMPA directly inhibits the activity of the Na+/H+ exchanger 1 (NHE1) in the cardiomyocytes to regulate excessive autophagy. Knockdown of NHE1 significantly rescued glucose deprivation-induced autosis. In contrast, overexpression of NHE1 aggravated the cardiomyocytes death in response to starvation, which was effectively rescued by EMPA treatment. Furthermore, in vitro and in vivo analysis of NHE1 and Beclin 1 knockout mice validated that EMPA's cardioprotective effects are at least in part through downregulation of autophagic flux. These findings provide new insights for drug development, specifically targeting NHE1 and autosis for ventricular remodeling and heart failure after MI in both diabetic and non-diabetic patients.

Ação dos isglt2 no hipertenso diabético, quando indicar? / Effect of sglt-2 inhibitor in diabetic hypertensive patients, when to indicate?

A doença cardiovascular (DCV) representa um fardo individual e social em pacientes com diabetes mellitus tipo 2 (DM2). A diabetes é uma doença crônica onerosa do ponto de vista social e econômico. O seu tratamento inclui medidas não farmacológicas, como dieta e exercício físico, bem como a adição de medicamentos em pacientes que não atingem controle glicêmico satisfatório através de medidas comportamentais. Medicamentos da classe inibidores de SGLT2 (iSGLT2), objeto deste manuscrito, têm sido associados com a redução de eventos cardiovasculares e mortalidade, além de redução da pressão arterial e peso, sem conferir aumento de risco de hipoglicemia

Cardiovascular disease (CVD) represents an individual and social burden in patients with type 2 diabetes mellitus (T2DM). Diabetes is a chronic, socially and economically costly disease. Its treatment includes non-pharmacological measures, such as diet and exercise, as well as the addition of medication in patients who do not achieve satisfactory glycemic control through behavioral approach. Drugs as SGLT2 inhibitor (SGLT2i), object of this manuscript, have been associated with a reduction in cardiovascular events and mortality, in addition to a reduction in blood pressure and weight, without increasing the risk of hypoglycemia.

Excavation and Evaluation of ADR Signals of SGLT 2 Inhibitors / 中国药房

OBJECTIVE：To excavate and evaluate ADR signals of SGLT 2 inhibitors as canagliflozin ，dapagliflozin and empagliflozin，and to provide reference for rational drug use in the clinic. METHODS ：The proportional reporting ratio （PRR）and reporting odds ratio （ROR）were used to find the adverse drug reactions （ADR）signal of SGLT 2 inhibitors as canagliflozin ， dapagliflozin and empagliflozin from the second quarter of 2013 to the third quarter of 2020 in the US FDA Adverse Event Reporting System （FAERS）. The basic information （including gender ，age，reporting year ，reporting country ，severe ADR ）and safety warning signals of corresponding patients in ADR report were analyzed. RESULTS ：Among 6 029 375 ADR reports ，SGLT2 inhibitors of 43 807 ADR reports were concomitant and suspected drugs ；there were 19 301 ADR reports of canagliflozin ，10 960 ADR reports of dapagliflozin ，13 546 ADR reports of empagliflozin. Except for the ADR patients with unknown gender and missing age ，the gender distribution of the included reports was balanced ，mainly in the range of 50-75 years old. The reporting year was mainly in 2018，and the main reporting country was the United States ，with“hospitalization or prolonged hospitalization ” as the main serious ADR. A total of 573 ADR signals were obtained ，involving 26 systems，mainly focusing on metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system disease ，infection and invasion diseases ，etc. The results showed that there were 14 main ADR signals in the top 10 ADR of canagliflozin ，dapagliflozin and empagliflozin. The strongest ADR signals of dapagliflozin and empagliflozin were ketoacidosis （PRR＝119.64/140.11，95％CI lower limit of ROR ＝148.28/ 178.78）and fungal infection （PRR＝47.76/34.77，95％ CI lower limit of ROR ＝50.69/36.28）；except above signals in addition ， toe amputation （PRR＝489.79，95％CI lower limit of ROR ＝520.15）and osteomyelitis （PRR＝61.42，95％CI lower limit of ROR＝65.38）were strong in the ADR signals of canagliflozin. CONCLUSIONS ：SGLT2 inhibitors have a higher security risk in metabolic and nutritional diseases ，endocrine disorders ，kidney and urinary system ，and infection and intrusion diseases. Dapagliflozin，canagliflozin and empag liflozin are prone to cause ADR such as ketoacidosis and fungal infection ，while canagliflozin is easy to cause ADRs such as toe amputation and osteomyelitis.

Reducing the risk of heart failure in diabetes mellitus: review of new therapeutics

Diabetes mellitus (DM) and heart failure (HF) are closely related: patients with diabetes have an increased risk of developing HF and those with HF are at higher risk of developing diabetes. When the two diseases are considered individually, HF has a much poorer prognosis than diabetes mellitus; therefore, treatment of HF is a priority in these group of patients. There are many drugs now available to achieve glycemic control in individuals with DM. However, as we enter an era of personalization in the management of DM, the next challenge will be the identification of therapeutic strategies that will not only achieve and maintain glycemic control, but that will also reverse existing complications. Given the high prevalence of HF in DM, there is a strong imperative to advance this field, with the view of identifying robust strategies that will not only improve long-term outcomes in subjects with DM and HF but also limit the likelihood of developing HF in the first place. Newer therapies like sodium- glucose transport protein- 2 inhibitors (SGLT-2 I) and sacubitril or valsartan have shown potential benefit for reducing the risk of heart failure in diabetic population. This review will summarize the new therapeutics to reduce the risk of HF in patients with DM.

Advances in cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists / 药学实践杂志

Type 2 diabetes is a high risk factor for atherosclerotic cardiovascular disease. Studies have found that SGLT-2 inhibitor and GLP-1 receptor agonists have cardiovascular protective effects in patients with type 2 diabetes and cardiovascular disease. Therefore, from the aspects of cardiovascular safety test and its Meta-analysis and net-like Meta-analysis, the research progress of cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists is summarized.

Need of the hour: pharmacovigilance study of SGLT-2 inhibitors

Background: Diabetes mellitus represents a global pandemic. Various pharmacotherapy and non-pharmacotherapy measures are advocated for its control. The latest in the pharmacotherapy are Sodium Glucose Transporter -2 (SGLT-2) inhibitors, widely used. Many studies suggest adverse effects related to SGLT-2 inhibitors, evidence still not conclusive and few data from India. Hence this study was planned.Methods: Cross-sectional study over a period of 02 months, recorded demographic details and history of various adverse drug reactions reported with the use of SGLT-2 inhibitors.Results: Majority of the study participants were females (58%) and belonged to the age group of 40-70 yrs. Urinary tract infections (UTI) and genital infections was more seen in the users of dapagliflozin, followed by empagliflozin and canagliflozin.Conclusions: SGLT-2 Inhibitors offer a unique therapeutic approach to the management of Diabetes Mellitus. Further evaluation of the safety profile and the risk-benefit analysis is the need of the hour.

Evaluation and comparison of anti-cancer activity of dapagliflozin and canagliflozin in oral cancer cell line: an in vitro study

Background: Cancer is rapidly evolving life-threatening ailment in the mankind due to changes in daily food intake and lifestyle changes. Oral carcinoma is 6th major cause of cancer death in the world and it is third major reason of cancer mortality in India. Every cell in the human body requires glucose for its metabolic energy. Besides normal cell, cancer cells also require the glucose for its endurance and multiplication. SGLT2 inhibitors which are aimed at diabetes therapy exhibited anticancer properties also in colon and pancreatic cancer lines. Present study aim is to evaluate the anticancer activity of SGLT2 inhibitors against oral cancer cell by MTT Assay.Methods: To evaluate the anticancer activity of SGLT2 inhibitors MTT Cytotoxic assay is performed as per standard protocols. Cancer cells were plated in 24-well plates and incubated at 370C with 5% CO2 condition. After convergence, samples are added to the plates in various concentrations and allowed to incubate then they are detached from the plates and cleansed with the reagents. The wells are coated with the dye and incubated. Later samples are analysed in UV-spectrophotometer.Results: Cytotoxic assay showed decrease in cell viability with increasing dose of SGLT2 inhibitors. IC50 values were determined graphically. The IC50 value of dapagliflozin is 400礸/ml and canagliflozin is 250礸/ml respectively after 24 hours of Assessment.Conclusions: The results of the current study give us an evidence that SGLT2 inhibitors dapagliflozin and canagliflozin exhibits anticancer property in Oral Cancer cell line.

Complications of Diabetes Mellitus: Prevention in Type 2 Diabetes Mellitus

@#Type 2 Diabetes Mellitus is a complex disorder which has many associated comorbidities besides hyperglycaemia. Micro and macrovascular complications develop as a result of poor risk factor control and contribute to the disability, reduced quality of life and reduced life expectancy associated with the disease. Intensive glucose control and, more importantly, comprehensive care involving treatment of all modifiable cardiovascular risk factors over a sustained period decreases the risk of morbidity and mortality especially in people newly diagnosed with Type 2 Diabetes Mellitus. The need to recognise subgroups of people with diabetes with increased risks of complications and the importance of individualised treatment are also discussed. Early intensive treatment and control of risk factors provides the opportunity for greatest accrual of benefit over the longer term.

Empagliflozin: an exciting prospect in the treatment of diabetes

Type 2 diabetes mellitus (T2DM) continues to be a chronic and disabling disease that is associated with high mortality and morbidity. The epidemic burden of diabetes mellitus has increased in developing countries and Asia is considered as the “diabetic epicentre”. Type 2 diabetes (T2DM), is characterised by reduced secretion of insulin from pancreatic beta cells independently or associated with reduced response of peripheral tissues to circulating insulin. A proper glycaemic control is essential to delay the micro and macrovascular complications of T2DM. Standard anti-diabetic agents including insulin happen to induce minor to major adverse outcomes in certain populations over prolonged period of administration. Hence there has been a compelling need to develop newer and novel approach to treatment of T2DM. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel category of drugs that happen to reduce glycaemic overload by inducing glycosuria. The safety, efficacy and tolerability profile of these drugs were studied separately under various trials and was approved for use in August 2014 by US-FDA. This review is an attempt to describe the history of SGLT-2 inhibitors, their mechanism of action, safety and efficacy as well as its current status among anti-diabetic agents.

A Review on Efficacy and Safety of SGLT2 Inhibitors as Add-on Therapy with Metformin

BACKGROUND: The new type of diabetes treatment, SGLT2 inhibitors, has been approved for monotherapy and combination therapy, but medical insurance is only allowed in combination therapy with metformin, which is the first choice for type 2 diabetes treatment. METHODS: The SGLT2 inhibitors prescribed in Korea are dapagliflozin, empagliflozin and ipragliflozin. A review was conducted using Pubmed to evaluate efficacy and safety for these medications with metformin combination therapy. 10 studies were selected by searching for keywords and related references and were reviewed in full. The mechanism of action, pharmacokinetics, and the economics of treatment with SGLT2 inhibitors were examined. RESULTS: SGLT2 inhibitors had moderate glycemic control when added to the treatment of patients with type 2 diabetes who were not being regulated by metformin monotherapy. They also showed positive effects such as weight loss, as well as the lowering of blood pressure. Hypotension and serious side effects were relatively low. However, the risk of genital infection was increased. CONCLUSION: The SGLT2 inhibitors are a new class of drugs that promote glucose excretion in the urine. They are a good choice for combination therapy with metformin for the treatment of type 2 diabetes, with weight loss and very low risk of serious side effects.

iSGLT2 y su potencial efecto nefroprotector en pacientes con diabetes mellitus 2 / iSGLT2 and its potential nephroprotector effect in patients with diabetes mellitus 2

Resumen: La diabetes mellitus 2 es una epidemia mundial, aunado a esto, la nefropatía diabética se ha convertido en la principal causa de insuficiencia renal en etapa terminal. En los pacientes con diabetes mellitus 2 existe sobreexpresión de los cotransportadores de glucosa ligados a la vía del sodio tipo 2 (SGLT2) que contribuyen al mantenimiento de la hiperglucemia. Por tanto, los inhibidores de este transportador representan un tratamiento innovador independiente de la acción de la insulina o la función de las células beta pancreáticas. En estudios recientes se ha demostrado que los iSGLT2 tienen efectos benéficos en la microvasculatura, en especial en la progresión de la nefropatía diabética. Este efecto no sólo se debe a la mejora del control glucémico, sino también a efectos directos en el riñón. Los iSGLT2, al inducir la glucosuria, revierten la glucotoxicidad renal. En estudios experimentales se ha observado que, además, se reduce la hiperfiltración, así como los marcadores inflamatorios y fibróticos. También se ha visto reducción del volumen circulante efectivo y aumento en la actividad de bloqueadores del sistema renina-angiotensina-aldosterona (bloqueadores RAA) circulantes, creando así un efecto nefroprotector.

Abstract: Type 2 diabetes mellitus 2 (DM2) is already a worldwide epidemic, in addition, diabetic nephropathy has become the leading cause of end-stage renal failure. In patients with DM2 there is an increased expression of the sodium-glucose cotransporters 2 (SGLT2) that contribute to the maintenance of hyperglycemia. Therefore, the inhibitors of this transporter represent an innovative therapy independent of the action of insulin or the function of pancreatic beta cells. Recent studies have shown that iSGLT2 have beneficial effects on microvasculature, especially in the progression of diabetic nephropathy. This effect is due not only to improved glycemic control but also to direct effects on the kidney. iSGLT2 induce glycosuria to reverse renal glucotoxicity. In experimental studies it has been observed that, in addition, hyper-filtration as well as inflammatory and fibrotic markers are reduced. There has also been a reduction in effective circulating volume and an increase in the activity of circulating renin-angiotensin-aldosterone system blockers (RAA blockers), thus creating a nephroprotective effect.

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus / Uso dos inibidores da SGLT-2 no tratamento do diabetes mellitus tipo 2

Summary Introduction: Diabetes mellitus is one of the most common chronic diseases in the world, with high morbidity and mortality rates, resulting in a greatly negative socioeconomic impact. Although there are several classes of oral antidiabetic agents, most of the patients are outside the therapeutic goal range. Objective: To review the use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus, focusing on their favorable and unfavorable effects, as well as on cardiovascular profile. Method: A literature search on Pubmed database was performed using the following keywords: "SGLT-2 inhibitors," "dapagliflozin," "empagliflozin," "canagliflozin." Results: SGLT-2 inhibitors are a class of oral antidiabetic drugs directed to the kidney. Their mechanism of action is to reduce blood glucose by inducing glycosuria. Extra-glycemic benefits have been described, such as weight loss, decline in blood pressure and levels of triglycerides and uric acid, and they can slow the progression of kidney disease. Genitourinary infections are the main side effects. There is a low risk of hypotension and hypoglycemia. Diabetic ketoacidosis is a serious adverse effect, although rare. Empagliflozin has already had its cardiovascular benefit demonstrated and studies with other drugs are currently being performed. Conclusion: SGLT-2 inhibitors are a new treatment option for type 2 diabetes mellitus, acting independently of insulin. They have potential benefits other than the reduction of blood glucose, but also carry a risk for adverse effects.

Resumo Introdução: O diabetes mellitus é uma das doenças crônicas mais frequentes no mundo, com altas taxas de morbimortalidade, resultando em um grande impacto negativo socioeconômico. Apesar de existirem diversas classes de antidiabéticos orais, a maioria dos pacientes acometidos está fora da meta terapêutica. Objetivo: Revisar o uso dos inibidores da SGLT-2 no tratamento do diabetes mellitus tipo 2, com enfoque nos efeitos favoráveis, desfavoráveis e no perfil cardiovascular. Método: Foi realizada uma pesquisa bibliográfica transversal com artigos científicos obtidos da base de dados Pubmed, utilizando os descritores: "SGLT-2 inhibitors", "dapagliflozin", "empagliflozin", "canagliflozin". Resultados: Os inibidores da SGLT-2 são uma classe de antidiabéticos orais com atuação no rim. O mecanismo de ação é reduzir a glicemia induzindo glicosúria. Benefícios extraglicêmicos já foram descritos, como redução de peso, pressão arterial, triglicerídeos e ácido úrico, além de retardar a progressão da doença renal. O principal efeito colateral é a infecção geniturinária, com baixo risco de hipotensão e hipoglicemia. Cetoacidose diabética é um efeito adverso grave, mas infrequente. A empagliflozina já teve seu benefício cardiovascular demonstrado, e estudos com outras drogas estão em andamento. Conclusão: Os inibidores da SGLT-2 são uma nova opção de tratamento do diabetes mellitus tipo 2, que atua de forma insulino-independente e com potenciais benefícios adicionais, além da redução da glicemia, mas também com risco de efeitos adversos.

A new synthetic process of dapagliflozin / 中国药科大学学报

This paper describes a practical process for a SGLT2 inhibitor dapagliflozin. The target product was synthesized from 1-chloro-2-( 4-ethoxybenzyl)-4-iodobenzene and 2, 3, 4, 6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide by iodine-magnesium exchange, and coupling and acetyl removing reactions with the total yield of 50%. This practical process highlights fewer reaction steps, less waste and mild reaction conditions.

The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) Trial and Its Clinical Impact on Patterns of Prescription for Anti-Diabetes Medication / 임상당뇨병

Since 2008, the Food and Drug Administration has required cardiovascular (CV) safety trials for all anti-diabetic medications available in the USA. Thus, new agents like dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists have been tested in CV safety trials. The results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) were released last year. Of the sodium-glucose cotransporter 2 (SGLT2) inhibitors tested, empagliflozin demonstrated a CV benefit in this trial. Another study of the renal protective effects of empagliflozin was released this year. The mechanisms supporting the cardio- and reno-protective effects of empagliflozin remain controversial. Hemodynamic changes related to SGLT2 inhibitors via natriuresis and osmotic diuresis are one potential mechanism. The Canadian Diabetes Association and European Society of Cardiology recently suggested SGLT2 inhibitors as an optimal anti-diabetic medication for patients with type 2 diabetes with overt CV disease. Further studies elucidating the potential mechanisms of cardio- and reno-protective effects of SGLT2 are needed.